This invention is in the field of antiinflammatory pharmaceutical agents and specifically relates to compounds, compositions and methods for treating inflammation and inflammation-associated disorders, such as arthritis.
Prostaglandins play a major role in the inflammation process and the inhibition of prostaglandin production, especially production of PGG2, PGH2 and PGE2, has been a common target of antiinflammatory drug discovery. However, common non-steroidal antiinflammatory drugs (NSAIDS) that are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process are also active in affecting other prostaglandin-regulated processes not associated with the inflammation process. Thus, use of high doses of most common NSAIDs can produce severe side effects, including life threatening ulcers, that limit their therapeutic potential. An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long term therapy is involved.
Previous NSAIDs have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cyclooxygenase (COX). The recent discovery of an inducible enzyme associated with inflammation (named xe2x80x9ccyclooxygenase-2 (COX-2)xe2x80x9d or xe2x80x9cprostaglandin G/H synthase IIxe2x80x9d) provides a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects.
The references below that disclose antiinflammatory activity, show continuing efforts to find a safe and effective antiinflammatory agent. The novel imidazoles disclosed herein are such safe and also effective antiinflammatory agents furthering such efforts. The invention compounds are found to show usefulness in vivo as antiinflammatory agents with minimal side effects. The substituted imidazoles disclosed herein preferably selectively inhibit cyclooxygenase-2 over cyclooxygenase-1.
U.S. Pat. No. 4,822,805, to Takasugi et al., describes pyridyl-imidazoles as antiinflammatory agents. Specifically, 2-[2-methoxy-4-(methylsulfonyl)phenyl-4-methyl-5-(3-pyridyl) imidazole is described.
U.S. Pat. No. 4,188,397, to Hill, describes 2,2-alkyldiylbis(thio)bis(imidazoles) with substituted phenyl radicals at the 4 and 5 positions of the imidazole rings as having antiinflammatory activity. Specifically, imidazoles having phenyl radicals substituted with methoxy, methylthio, trifluoromethylhalo and methylenedioxy are described.
T. Sharpe et al. [J.Med. Chem., 28, 1188 (1985)] describe antiarthritic activity of 4,5-diaryl-2-(substituted thio)-1H-imidazoles.
U.S. Pat. No. 4,686,231, to Bender et al., describes 4,5-diaryl-1H-imidazoles as inhibiting the 5-lipoxygenase pathway for the treatment of arthritis. 1-Methyl-4,5-bis(methoxyphenyl)-2-methylthio-1H-imidazole is specifically described.
Australian publication AU8665565 describes cyano-2,2-bis(imidazoles) as having antihypertensive agents.
WO 93/14082, published Jul. 22, 1993, describes 1-pyridyl-2-phenyl-imidazole derivatives for the treatment of interleukin-1 mediated diseases.
H. Greenberg et al. [J.Org.Chem., 31, 3951 (1966)] describe 4-(2-oxo-5-phenyl-4-imidazolin-4-yl)benzenesulfonamide in a study of the bromination reaction thereof.
T. van Es and O. Backeberg [J. Chem. Soc., 1363 (1963)] describe the synthesis of 4,4xe2x80x2-imidazol-4,5-diyl]bis(benzenesulfonamide) for use in a study of substitution reactions on phenyl radicals.
European publication EP 372,445, published Jun. 13, 1990, describes 4,5-diaryl-1H-imidazoles as having antihypercholesterolemic activity. N-C[[5-(4-Methylsulfonylphenyl)-4-phenyl-1H-imidazol-2-yl]thio]pentyl-N-octyl-N-heptylurea is specifically described. U.S. Pat. No. 5,364,875, to Wilde, describes substituted imidazoles for the treatment of atherosclerosis. U.S. Pat. No. 5,358,946, to Wilde, describes substituted imidazoles for the treatment of atherosclerosis. U.S. Pat. No. 5,310,748, to Billheimer et al., describes substituted imidazoles for the treatment of atherosclerosis. U.S. Pat. No. 5,166,214, to Billheimer et al., describes substituted imidazoles for the treatment of atherosclerosis. T. Maduskuie et al., [J. Med. Chem., 38, 1067 (1995)] describes substituted imidazoles as acyl-CoA:Cholesterol Acyltransferase inhibitors
U.S. Pat. No. 4,503,065, to Wilkerson, describes 4,5-diaryl-2-halo-1H-imidazoles as being antiinflammatory. Specifically, 1-(1-ethoxyethyl)-2-fluoro-4,5-bis(4-methylsulfonylphenyl)-1H-imidazole is described.
J. Lombardino (J. Med. Chem., 17, 1182 (1974)) describes trisubstituted imidazoles as being antiinflammatory, and specifically 4,5-bis(4-methoxyphenyl)-2-trifluoromethyl-1H-imidazole. Similarly, U.S. Pat. No. 3,707,475, to Lombardino, describes antiinflammatory 4,5-diarylimidazoles. Specifically, 4-chlorophenyl-5-(4-methylthiophenyl)-2-trifluoromethyl-1H-imidazole is described.
U.S. Pat. No. 4,472,422, to Whitney, describes 4,5-diaryl-1H-imidazole-2-methanamines as having antiinflammatory activity. Specifically, 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-xcex1,xcex1-bis(trifluoromethyl)-1H-imidazole-2-methanamine is described.
U.S. Pat. No. 4,372,964, to Whitney, describes 4,5-diaryl-1H-imidazole-2-methanols as having antiinflammatory activity. Specifically, 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-xcex1,xcex1-bis(trifluoromethyl)-1H-imidazole-2-methanol is described. Additionally, Whitney describes 1-[4,5-diaryl-1H-imidazol-2-yl]-2,2,2-trifluoro-1-ethanones as having antiinflammatory activity. Specifically, 1-[5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-1H-imidazol-2-yl]-2,2,2-trifluoro-1-ethanone is described.
U.S. Pat. No. 4,576,958, to Wexler, describes 4-phenyl-5-(4-methylsulfonylphenyl)-1H-imidazoles as having antiinflammatory activity. Specifically, 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-xcex1,xcex1-bis(trifluoromethyl)-1H-imidazole-2-methanol and 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-xcex1,xcex1-bis(trifluoromethyl)-1H-imidazole-2-methanol, acetate is described. U.S. Pat. No. 4,632,930, to Carini et al., claims cycloalkyl substituted imidazoles, and specifically 4-cyclopentyl-5-(4-methylsulfonyl)-xcex1,xcex1-bis(trifluoromethyl)-1H-imidazole-2-methanol, as having antihypertensive properties.
U.S. Pat. No. 3,901,908, to Fitzi, et al., describes 2-alkyl-4,5-bis(substituted phenyl)-1H-imidazoles. Specifically, 2-tert-butyl-4-(4-methylsulfonylphenyl)-5-phenyl-1H-imidazole is described. French patent 2,081,407 describes 4,5-phenyimidazoles as antiinflammatory agents.
4,5-Diarylimidazoles have been described in WO95/00501, published Jan. 5, 1995, as having antiinflammatory activity.
The invention""s imidazolyl compounds are found to show usefulness in vivo as antiinflammatory agents with minimal side effects.
A class of substituted imidazolyl compounds useful in treating inflammation-related disorders is defined by Formula I: 
wherein R1 is selected from alkyl, haloalkyl, aralkyl, heterocyclicalkyl, heteroaralkyl, acyl, cyano, mercapto, alkoxy, alkylthio, alkylthioalkyl, alkylsulfonyl, haloalkylsulfonyl, arylsulfonyl, halo, hydroxyalkyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, cyanoalkyl, aralkenyl, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-alkyl-N-aryl-aminoalkyl, carboxyalkyl, alkoxycarbonylalkyl, alkoxycarbonyl, haloalkylcarbonyl, carboxyl, alkoxyalkyl, alkenyloxyalkyl, aminocarbonyl, alkylaminocarbonyl, alkylaminocarbonylalkyl, heteroaralkoxyalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, heteroarylalkylthioalkyl, aralkoxy, aralkylthio, heteroaralkoxy, heteroaralkylthio, heteroaryloxy, heteroarylthio, arylthioalkyl, arylsulfonyl, aralkylsulfonyl, heteroarylsulfonyl, heteroarylalkylsulfonyl, aryloxyalkyl, arylthio, aryloxy, aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, aryl and heteroaryl, wherein the aryl and heteroaryl radicals are optionally substituted at a substitutable position with one or more radicals selected from halo, alkylthio, alkylsulfinyl., alkyl, cyano, haloalkyl, hydroxyl, alkoxy, hydroxyalkyl and haloalkoxy;
wherein R2 and R3 are independently selected from cycloalkyl, cycloalkenyl, heterocyclo and aryl, wherein the cycloalkyl, cycloalkenyl, heterocyclo and aryl radicals are substituted with one or more radicals selected from hydrido, halo, alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, haloalkylsulfonyl, alkyl, cyano, carboxyl, alkoxycarbonyl, haloalkyl, hydroxyl, alkoxy, hydroxyalkyl, alkoxyalkyl, haloalkoxy, amino, alkylamino, arylamino and nitro; and
wherein R4 is selected from hydrido, alkyl and acyl;
provided one of R2 and R3 is phenyl substituted with a radical selected from alkylsulfonyl or aminosulfonyl; further provided R1 is not xcex1,xcex1-bis(trifluoromethyl)methanol, xcex1,xcex1-bis(trifluoromethyl) methanamine, xcex1,xcex1-bis(trifluoromethyl)methanol, acetate ester, or trifluoroacetyl when R3 is 4-methylsulfonylphenyl and when R1 is hydrido; and further provided R1 is not alkyl when R3 is 4-methylsulfonylphenyl and R2 is phenyl optionally substituted with methyl, methoxy or chloro; or a pharmaceutically-acceptable salt thereof.
The phrase xe2x80x9cfurther providedxe2x80x9d, as used in the above description, is intended to mean that the denoted proviso is not to be considered conjunctive with any of the other provisos.
Compounds of Formula I would be useful for, but not limited. to, the treatment of inflammation in a subject, and for treatment of other inflammation-associated disorders, such as, as an analgesic in the treatment of pain and headaches, or as an antipyretic for the treatment of fever. For example, compounds of the invention would be useful to treat arthritis, including but not limited to rheumatoid arthritis, spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis. Such compounds of the invention would be useful in the treatment of asthma, bronchitis, menstrual cramps, tendinitis, bursitis, and skin related conditions such as psoriasis, eczema, burns and dermatitis. Compounds of the invention also would be useful to treat gastrointestinal conditions such as inflammatory bowel disease, Crohn""s disease, gastritis, irritable bowel syndrome and ulcerative colitis and for the prevention of colorectal cancer. Compounds of the invention would be useful in treating inflammation in such diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin""s disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet""s syndrome, polymyositis, gingivitis, hypersensitivity, conjunctivitis, swelling occurring after injury, myocardial ischemia, and the like. The compounds were also be useful in the treatment of ophthalmic diseases such as retinitis, retinopathies, uveitis, and of acute injury to the eye tissue. The compounds would also be useful for the treatment of certain central nervous system disorders such as Alzheimer""s disease and dementia. The compounds of the invention are useful as anti-inflammatory agents, such as for the treatment of arthritis, with the additional benefit of having significantly less harmful side effects. These compounds would also be useful in the treatment of allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis and central nervous system damage resulting from stroke, ischemia and trauma.
Besides being useful for human treatment, these compounds are also useful for treatment of mammals, including horses, dogs, cats, rats, mice,. sheep, pigs, etc.
The present compounds may also be used in co-therapies, partially or completely, in place of other conventional antiinflammatories, such as together with steroids, NSAIDs, 5-lipoxygenase inhibitors, LTB4 antagonists and LTA4 hydrolase inhibitors.
Suitable LTB4 inhibitors include, among others, ebselen, Bayer Bay-x-1005, Ciba Geigy compound CGS-25019C, Leo Denmark compound ETH-615, Lilly compound LY-293111, Ono compound ONO-4057, Terumo compound TMK-688, Lilly compounds LY-213024, 264086 and 292728, ONO compound ONO-LB457, Searle compound SC-53228, calcitrol, Lilly compounds LY-210073, LY223982, LY233469, and LY255283, ONO compound ONO-LB-448, Searle compounds SC-41930, SC-50605 and SC-51146, and SKandF compound SKF-104493. Preferably, the LTB4 inhibitors are selected from ebselen, Bayer Bay-x-1005, Ciba Geigy compound CGS-25019C, Leo Denmark compound ETH-615, Lilly compound LY-293111, Ono compound ONO-4057, and Terumo compound TMK-688.
Suitable 5-LO inhibitors include, among others, masoprocol, tenidap, zileuton, pranlukast, tepoxalin, rilopirox, flezelastine hydrochloride, enazadrem phosphate, and bunaprolast.
As, illustrated, the imidazoles of Formula II and IIxe2x80x2 are magnetically and structurally equivalent because of the prototropic tautomeric nature of the acidic hydrogen (A. R. Katritzky and C. W. Rees, xe2x80x9cImidazoles and their Benzo Derivativesxe2x80x9d Comprehensive Heterocyclic Chemistry, Vol. 5, 363-365 (1984)]: 
The present invention preferably includes compounds which selectively inhibit cyclooxygenase II over cyclooxygenase I. Preferably, the compounds have a cyclooxygenase II IC50 of less than about 0.5 xcexcM, and also have a selectivity ratio of cyclooxygenase II inhibition over cyclooxygenase I inhibition of at least 5, and more preferably of at least 100. Even more preferably, the compounds have a cyclooxygenase I IC50 of greater than about 2.5 xcexcM, and more preferably of greater than 50 xcexcM. Such preferred selectivity may indicate an ability to reduce the incidence of common NSAID-induced side effects.
A preferred class of compounds consists of those compounds of Formula I wherein R1 is selected from lower alkyl, lower haloalkyl, lower aralkyl, lower heterocyclicalkyl, lower heteroaralkyl, acyl, cyano, mercapto, lower alkoxy, lower alkylthio, lower alkylthioalkyl, lower alkylsulfonyl, lower haloalkylsulfonyl, lower arylsulfonyl, halo, lower hydroxyalkyl, lower alkoxyalkyl, lower alkenyloxyalkyl, lower alkylcarbonyl, lower arylcarbonyl, lower aralkylcarbonyl, lower cyanoalkyl, lower aralkenyl, lower aminoalkyl, lower alkylaminoalkyl, lower N-arylaminoalkyl, lower N-alkyl-N-arylaminoalkyl, lower carboxyalkyl, lower alkoxycarbonylalkyl, lower alkoxycarbonyl, lower haloalkylcarbonyl, carboxyl, aminocarbonyl, lower alkylaminocarbonyl, lower alkylaminocarbonylalkyl, lower aralkoxy, lower aralkylthio, phenylsulfonyl, lower aralkylsulfonyl, lower heteroaralkoxy, lower heteroaralkylthio, lower heteroarylalkoxyalkyl, lower heteroaryloxyalkyl, lower heteroarylthioalkyl, lower heteroarylalkylthioalkyl, heteroaryloxy, heteroarylthio, lower arylthioalkyl, lower aryloxyalkyl, lower arylthio, aryloxy, lower aralkylthioalkyl, lower aralkoxyalkyl, lower alkoxyaralkoxyalkyl, aryl and heteroaryl, wherein the aryl and heteroaryl radicals are optionally substituted at a substitutable position with one or more radicals selected from halo, lower alkylthio, lower alkylsulfinyl, lower alkyl, cyano, lower haloalkyl, lower hydroxyl, lower alkoxy, lower hydroxyalkyl and lower haloalkoxy; wherein R2 and R3 are independently selected from heteroaryl, lower cycloalkyl, lower cycloalkenyl, and aryl, wherein the heteroaryl, lower cycloalkyl, lower cycloalkenyl, and aryl radicals are substituted with one or more radicals selected from hydrido, halo, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, aminosulfonyl, lower haloalkylsulfonyl, lower alkyl, cyano, carboxyl, lower alkoxycarbonyl, lower haloalkyl, hydroxyl, lower alkoxy, lower hydroxyalkyl, lower alkoxyalkyl, lower haloalkoxy, amino, lower alkylamino, arylamino and nitro; and wherein R4 is selected from hydrido, lower alkyl and acyl; or a pharmaceutically-acceptable salt thereof.
A more preferred class of compounds consists of those compounds of Formula I wherein R1 is selected from lower alkyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower alkenyloxyalkyl, mercapto, lower alkylcarbonyl, lower haloalkylcarbonyl, phenylcarbonyl, lower aralkylcarbonyl, lower aralkenyl, lower aryloxyalkyl, lower aralkyloxyalkyl, lower arylsulfonyl, lower aralkylsulfonyl, lower arylthioalkyl, lower heteroarylalkylthioalkyl, and heteroaryl selected from 2-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 4-pyridyl and 2-benzdfuryl; wherein R2 and R3 are independently selected from heteroaryl, cycloalkyl and aryl, wherein the heteroaryl, cycloalkyl and aryl radicals are substituted at a substitutable position with one or more radicals selected from hydrido, halo, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, aminosulfonyl, lower alkyl, cyano, carboxyl, lower alkoxycarbonyl, lower haloalkyl, hydroxyl, lower alkoxy, lower hydroxyalkyl, lower alkoxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino and nitro; and wherein R4 is selected from hydrido, lower-alkyl and acyl; or a pharmaceutically-acceptable salt thereof.
A class of compounds of particular interest consists of those compounds of Formula I wherein R1 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, mercapto, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, ethoxymethyl, propylenyloxymethyl, methylcarbonyl, trifluoromethylcarbonyl, phenylcarbonyl, benzylcarbonyl, phenylethylcabonyl, phenylpropylcarbonyl, 2-bromo-benzylcarbonyl, 2-phenylethenyl, phenoxymethyl, benzyloxymethyl, phenylthiomethyl, quinolylmethylthiomethyl, phenylsulfonyl, benzylsulfonyl, 3-furyl, 2-furyl, 2-benzofuryl; wherein R2 and R3 are independently selected from phenyl, naphthyl, biphenyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, benzofuryl, benzodioxolyl, furyl, imidazolyl, thienyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, pyrimidinyl, quinolinyl, benzimidazolyl, indolyl, pyrazolyl and pyridyl, wherein R2 and R3 are substituted at a substitutable position with one or more radicals selected from hydrido, fluoro, chloro, bromo, iodo, methyl, ethyl, isopropyl, tert-butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, methylsulfonyl, aminosulfonyl, cyano, methoxy, ethoxy, isopropoxy, tert-butoxy, propoxy, butoxy, isobutoxy, pentoxy, methylenedioxy, amino, trifluoromethoxy, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, pentoxycarbonyl, hydroxyl, nitro, methylsulfinyl, butylsulfinyl, hydroxymethyl, methoxymethyl, ethoxymethyl, methylamino, N,N-dimethylamino, phenylamino, methylthio, ethylthio, propylthio and butylthio; and wherein R4 is selected from methyl, ethyl, hydrido, methylcarbonyl and trifluoromethylcarbonyl; or a pharmaceutically-acceptable salt thereof.
A family of specific compounds of particular interest within Formula I consists of compounds and pharmaceutically-acceptable salts thereof as follows:
5-(3-chlorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethyl-1H-imidazole;
5-(3-chloro-4-methylphenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethyl-1H-imidazole;
5-(3-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethyl-1H-imidazole;
5-(3-chloro-4-methoxyphenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethyl-1H-imidazole;
5-(2,4-dichlorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethyl-1H-imidazole;
5-(4-bromophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethyl-1H-imidazole;
4-(4-methylsulfonylphenyl)-2-trifluoromethyl-5-(4-trifluoromethylphenyl)-1H-imidazole;
4-(4-methylsulfonylphenyl)-2-trifluoromethyl-5-(4-trifluoromethoxyphenyl)-1H-imidazole;
5-(4-ethylphenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethyl-1H-imidazole;
5-(4-butylphenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethyl-1H-imidazole;
5-(4-butoxyphenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethyl-1H-imidazole;
4-(4-methylsulfonylphenyl)-5-(4-methylthiophenyl)-2-trifluoromethyl-1H-imidazole;
5-(3,5-dichloro-4-methoxyphenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethyl-1H-imidazole;
5-(3,5-dichloro-4-methylphenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethyl-1H-imidazole;
5-[4-(4-methylsulfonylphenyl)-2-trifluoromethyl-1H-imidazol-5-yl]-1,3-benzodioxole;
2-(4-chlorophenoxy)methyl-5-(4-chlorophenyl)-4-(4-methylsulfonylphenyl)-1H-imidazole;
5-(4-chlorophenyl)-2-[(4-fluorophenoxy)methyl]-4-(4-methylsulfonylphenyl)-1H-imidazole;
5-(4-chlorophenyl)-4-(4-methylsulfonylphenyl)-2-(phenylthiomethyl)-1H-imidazole;
5-(4-chlorophenyl)-2-[(4-methoxybenzyloxy)methyl]-4-(4-methylsulfonylphenyl)-1H-imidazole;
2-benzyl-5-(4-chlorophenyl)-4-(4-methylsulfonylphenyl)-1H-imidazole;
5-(4-chlorophenyl)-4-(4-methylsulfonylphenyl)-2-(phenylethyl)-1H-imidazole;
5-(4-chlorophenyl)-4-(4-methylsulfonylphenyl)-2-(phenylcarbonyl)-1H-imidazole;
5-(4-chlorophenyl)-4-(4-methylsulfonylphenyl)-2-phenoxymethyl-1H-imidazole;
5-(4-chlorophenyl)-4-(4-methylsulfonylphenyl)-2-(2-phenyl-trans-eth-1-ene)-1H-imidazole;
2-(2-benzofuryl)-5-(4-chlorophenyl)-4-(4-methylsulfonylphenyl)-1H-imidazole;
5-(4-chlorophenyl)-4-(4-methylsulfonylphenyl)-2-(2-furyl)-1H-imidazole;
2-benzylthio-5-(4-chlorophenyl)-4-[4-(methylsulfonyl)phenyl]imidazole;
5-(4-chlorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
5-(4-chlorophenyl)-2-(3-furyl)-4-[4-(methylsulfonyl)phenyl]-1H-imidazole;
4-(4-methylsulfonylphenyl)-5-phenyl-2-phenoxymethyl-1H-imidazole;
4-(4-methylsulfonylphenyl)-5-phenyl-2-(2-phenyl-trans-eth-1-ene)-1H-imidazole;
2-(2-benzofuryl)-4-(4-methylsulfonylphenyl)-5-phenyl-1H-imidazole;
2-(2-furyl)-4-(4-methylsulfonylphenyl)-5-phenyl-1H-imidazole;
2-benzylthio-4-[4-(methylsulfonyl)phenyl]-5-phenyl-imidazole;
4-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazole;
2-(3-furyl)-4-[4-(methylsulfonyl)phenyl]-5-phenyl-1H-imidazole;
4-[5-(3-chlorophenyl)-2-trifluoromethyl-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(3-chloro-4-methylphenyl)-2-trifluoromethyl-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(3-fluorophenyl)-2-trifluoromethyl-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(3-chloro-4-methoxyphenyl)-2-trifluoromethyl-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(2,4-dichlorophenyl)-2-trifluoromethyl-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(4-bromophenyl)-2-trifluoromethyl-1H-imidazol-4-yl]benzenesulfonamide;
4-[2-trifluoromethyl-5-(4-trifluoromethylphenyl)-1H-imidazol-4-yl]benzenesulfonamide;
4-[2-trifluoromethyl-5-(4-trifluoromethoxyphenyl)-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(4-ethylphenyl)-2-trifluoromethyl-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(4-butylphenyl)-2-trifluoromethyl-1H-imidazol-4yl]benzenesulfonamide;
4-[5-(4-butoxyphenyl)-2-trifluoromethyl-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(4-methylthiophenyl)-2-trifluoromethyl-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(3,5-dichloro-4-methoxyphenyl)-2-trifluoromethyl-1H-imidazol-4-yl]benzenesulfonamide;
5-(3,5-dichloro-4-methylphenyl)-2-trifluoromethyl-1H-imidazol-4yl]benzenesulfonamide;
5-[4-(4-aminosulfonylphenyl)-2-trifluoromethyl-1H-imidazol-5-yl]-1,3-benzodioxole;
4-[2-(4-chlorophenoxy)methyl-5-(4-chlorophenyl)-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-2-[(4-fluorophenoxy)methyl]-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-2-(phenylthiomethyl)-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-2-[(4-methoxybenzyloxy)methyl]-1H-imidazol-4-yl]benzenesulfonamide;
4-[2-benzyl-5-(4-chlorophenyl)-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-2-(phenylethyl)-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-2-(phenylcarbonyl)-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-2-phenoxymethyl-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-2-(2-phenyl-trans-eth-1-ene)-1H-imidazol-4-yl]benzenesulfonamide;
4-[2-(2-benzofuryl)-5-(4-chlorophenyl)-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-2-(2-furyl)-1H-imidazol-4-yl]benzenesulfonamide;
4-[2-benzylthio-5-(4-chlorophenyl)-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-2-(trifluoromethyl)-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-2-(3-furyl)-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-phenyl-2-phenoxymethyl-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-phenyl-2-(2-phenyl-trans-eth-1-ene)-1H-imidazol-4-yl]benzenesulfonamide;
4-[2-(2-benzofuryl)-5-phenyl-1H-imidazol-4-yl]benzenesulfonamide;
4-[2-(2-furyl)-5-phenyl-1H-imidazol-4-yl]benzenesulfonamide;
4-[2-benzylthio-5-phenyl-imidazol-4-yl]benzenesulfonamide;
4-[5-phenyl-2-(trifluoromethyl)-1H-imidazol-4-yl]benzenesulfonamide;
4-[2-(3-furyl)-5-phenyl-1H-imidazol-4-yl]benzenesulfonamide;
5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethyl-1H-imidazole;
5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-phenoxymethyl-1H-imidazole;
5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-(2-phenyl-trans-eth-1-ene)-1H-imidazole;
2-(2-benzofuryl)-5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-1H-imidazole;
5-(4-fluorophenyl)-2-(2-furyl)-4-(4-methylsulfonylphenyl)-1H-imidazole;
5-(4-fluorophenyl)-2-methyl-4-(4-methylsulfonylphenyl)-1H-imidazole;
5-(4-fluorophenyl)-2-isopropyl-4-(4-methylsulfonylphenyl)-1H-imidazole;
5-(4-fluorophenyl)-2-hydroxymethyl-4-(4-methylsulfonylphenyl)-1H-imidazole;
2-benzylthio-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]imidazole;
5-(3-fluoro-4-methoxyphenyl)-4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
5-(4-chlorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
5-(2-chlorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
5-(3,4-dichlorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
4-[4-(methylsulfonyl)phenyl]-5-(2-naphthyl)-2-(trifluoromethyl)-1H-imidazole;
5-(4-methoxyphenyl)-4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
5-(4-methylphenyl)-4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
5-(2,4-difluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
5-(3,4-difluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
4-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)-1H-imidazole;
5-(4-fluorophenyl)-2-(3-furyl)-4-(4-methylsulfonylphenyl)-1H-imidazole;
4-[5-(4-fluorophenyl)-2-(trifluoromethyl)-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(4-fluorophenyl)-2-phenoxymethyl-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(4-fluorophenyl)-2-(2-phenyl-trans-eth-1-ene)-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(4-fluorophenyl)-2-(2-benzofuryl)-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(4-fluorophenyl)-2-isopropyl-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(4-fluorophenyl)-2-methyl-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(4-fluorophenyl)-2-(2-furyl)-1H-imidazol-4-yl]benzenesulfonamide;
4-[2-benzylthio-5-(4-fluorophenyl)-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(4-fluorophenyl)-2-hydroxymethyl-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(3-fluoro-4-methoxyphenyl)-2-(trifluoromethyl)-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(4-chlorophenyl)-2-(trifluoromethyl)-1H-imidazol-
4-yl]benzenesulfonamide;
4-[5-(2-chlorophenyl)-2-(trifluoromethyl)-1H-imidazol-4-yl]benzenesulfonamide;
4-[5(-3,4-dichlorophenyl)-2-(trifluoromethyl)-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(2-naphthyl)-2-(trifluoromethyl)-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(4-methoxyphenyl)-2-(trifluoromethyl)-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(4-methylphenyl)-2-(trifluoromethyl)-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(2,4-difluorophenyl)-2-(trifluoromethyl)-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(3,4-difluorophenyl)-2-(trifluoromethyl)-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-phenyl-2-(trifluoromethyl)-1H-imidazol-4-yl]benzenesulfonamide;
4-[5-(4-fluorophenyl)-2-(3-furyl)-1H-imidazol-4-yl]benzenesulfonamide;
4-(3,4-dimethoxyphenyl)-5-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
4-(4-methoxy-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
5-(4-fluorophenyl)-1-methyl-4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
4-(4-fluorophenyl)-1-methyl-5-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
5-(3,5-dimethylphenyl)-4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
5-(5-bromothien-2-yl)-4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
N,N-dimethyl-4-[4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazol-5-yl]benzenamine;
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-1H-imidazole-2-thiol;
2-[[[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-1H-imidazol-2-yl]thio]methyl]quinoline;
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-[(phenylmethyl) sulfonyl]-1H-imidazole;
5-(3,5-dimethyl-4-methoxyphenyl)-4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
5-[3-fluoro-4-(methylthio)phenyl]-4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
5-(3-chloro-5-methylphenyl)-4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
5-[3-chloro-4-(methylthio)phenyl]-4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
5-(3-fluoro-4-methylphenyl)-4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
1-[5-(3-chloro-5-methylphenyl)-4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazol-1-yl]ethanone;
5-(3-methylphenyl)-4-(4-(methylsulfonyl)phenyl]-2-trifluoromethyl-1H-imidazole;
5-(3-methylphenyl)-4-[4-(sulfonamido)phenyl]-2-trifluoromethyl-1H-imidazole;
5-(3,4-dimethylphenyl)-4-[4-(methylthio)phenyl]-2-(trifluoromethyl)-1H-imidazole;
4-(4-(methylsulfonyl)phenyl]-5-(3-pyridyl)-2-(trifluoromethyl)-1H-imidazole;
5-(3-cyanophenyl)-4-[4-(methylthio)phenyl]-2-(trifluoromethyl)-1H-imidazole;
5-(2-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
5-(3-methoxyphenyl)-4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
5-(2-methylphenyl)-4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
5-(cyclohexyl)-4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
4-[4-(methylsulfonyl)phenyl]-5-(2-thiophenyl)-2-(trifluoromethyl)-1H-imidazole;
5-(4-chloro-3-methylphenyl)-4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
5-(4-cycloheptyl)-4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
5-(4-fluoro-3-methylphenyl)-4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
5-(cyclopentyl)-4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
4-[4-(methylsulfonyl)phenyl]-5-(3-thiophenyl)-2-(trifluoromethyl)-1H-imidazole;
5-(3-fluoro-2-methylphenyl)-4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
5-(4-chloro-3-methoxyphenyl)-4-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)-1H-imidazole;
5-(4-fluorophenyl)-2-(methoxymethyl)-4-[4-(methylsulfonyl)-phenyl]-1H-imidazole;
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-[(2-propenyloxy)methyl]-1H-imidazole;
2-(ethoxymethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-1H-imidazole;
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-(phenyl-methoxymethyl)-1H-imidazole;
1-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-1H-imidazol-2-yl]ethanone;
2-(2-bromophenyl)-1-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-1H-imidazol-2-yl]ethanone;
1-(4-(4-fluorophenyl)-5-[4-methylsulfonyl)phenyl]-1H-imidazol-2-yl]-3-phenyl-1-propanone;
1-[5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-1H-imidazol-2-yl]-2-phenylethanone;
[5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-1H-imidazol-2-yl]phenylmethanone;
1-[5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-1H-imidazol-2-yl]-4-phenyl-1-butanone;
2,2,2-trifluoro-1-[4-(4-fluorophenyl)-5-[4-methylsulfonyl)phenyl]-1H-imidazol-2-yl]ethanone;
4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-(phenyl-sulfonyl)-1H-imidazole;
4-(4-fluorophenyl)-xcex1-methyl-5-[4-(methylsulfonyl)phenyl]-1H-imidazole-2-methanol;
4-(4-fluorophenyl)-2-(1-methoxyethyl)-5-[4-(methylsulfonyl)phenyl]-1H-imidazole; and
2-(1,1-difluoroethyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-1H-imidazole.
Within Formula I there is a subclass of compounds of high interest represented by Formula II: 
wherein R1 is selected from lower alkyl, lower haloalkyl, lower aralkyl, lower heterocyclicalkyl, lower heteroaralkyl, acyl, cyano, mercapto, lower alkoxy, lower alkylthio, lower alkylthioalkyl, lower alkylsulfonyl, lower haloalkylsulfonyl, lower arylsulfonyl, halo, lower hydroxyalkyl, lower alkoxyalkyl, lower alkenyloxyalkyl, lower alkylcarbonyl, lower arylcarbonyl, lower aralkylcarbonyl, lower cyanoalkyl, lower aralkenyl, lower aminoalkyl, lower alkylaminoalkyl, lower N-arylaminoalkyl, lower N-alkyl-N-arylaminoalkyl, lower carboxyalkyl, lower alkoxycarbonylalkyl, lower alkoxycarbonyl, lower haloalkylcarbonyl, carboxyl, aminocarbonyl, lower alkylaminocarbonyl, lower alkylaminocarbonylalkyl, lower aralkoxy, lower aralkylthio, phenylsulfonyl, lower aralkylsulfonyl, lower heteroaralkoxy, lower heteroaralkylthio, lower heteroarylalkoxyalkyl, lower heteroaryloxyalkyl, lower heteroarylthioalkyl, lower heteroarylalkylthioalkyl, heteroaryloxy, heteroarylthio, lower arylthioalkyl, lower aryloxyalkyl, lower arylthio, aryloxy, lower aralkylthioalkyl, lower aralkoxyalkyl, lower alkoxyaralkoxyalkyl, aryl and heteroaryl, wherein the aryl and heteroaryl radicals are optionally substituted at a substitutable position with one or more radicals selected from halo, lower alkylthio, lower alkylsulfinyl, lower alkyl, cyano, lower haloalkyl, lower hydroxyl, lower alkoxy, lower hydroxyalkyl and lower haloalkoxy; wherein R2 is selected from heteroaryl, lower cycloalkyl, lower cycloalkenyl, and aryl, wherein the heteroaryl, lower cycloalkyl, lower cycloalkenyl, and aryl radicals are substituted with one or more radicals selected from hydrido, halo, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkyl, cyano, carboxyl, lower alkoxycarbonyl, lower haloalkyl, hydroxyl, lower alkoxy, lower hydroxyalkyl, lower alkoxyalkyl, lower haloalkoxy, amino, lower alkylamino, arylamino and nitro; and wherein R5 is selected from lower alkyl and amino; provided R1 is not lower alkyl when R5 is methyl and when R2 is phenyl or phenyl substituted with methyl, methoxy or chloro; or a pharmaceutically-acceptable salt thereof.
A preferred class of compounds consists of those compounds of Formula II wherein R1 is selected from lower heterocyclicalkyl, lower heteroaralkyl, acyl, cyano, mercapto, lower alkoxy, lower alkylthio, lower alkylthioalkyl, lower alkylsulfonyl, lower haloalkylsulfonyi, lower arylsulfonyl, halo, lower alkenyloxyalkyl, lower alkylcarbonyl, lower arylcarbonyl, lower aralkylcarbonyl, lower cyanoalkyl, lower aralkenyl, lower aminoalkyl, lower alkylaminoalkyl, lower N-arylaminoalkyl, lower N-alkyl-N-arylaminoalkyl, lower alkoxycarbonyl, lower haloalkylcarbonyl, aminocarbonyl, lower alkylaminocarbonyl, lower alkylaminocarbonylalkyl, lower aralkoxy, lower aralkylthio, phenylsulfonyl, lower heteroaralkoxy, heteroaryloxy, heteroarylthio, lower arylthioalkyl, lower aryloxyalkyl, lower arylthio, aryloxy, lower aralkylthioalkyl, lower aralkoxyalkyl, lower alkoxyaralkoxyalkyl, aryl and heteroaryl, wherein the aryl and heteroaryl radicals are optionally substituted at a substitutable position with one or more radicals selected from halo, lower alkylthio, lower alkylsulfinyl lower alkyl, cyano, lower haloalkyl, lower hydroxyl, lower alkoxy, lower hydroxyalkyl and lower haloalkoxy; wherein R2 is selected from heteroaryl, lower cycloalkyl, lower cycloalkenyl, and aryl, wherein the heteroaryl, lower cycloalkyl, lower cycloalkenyl, and aryl radicals are substituted with one or more radicals selected from hydrido, halo, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkyl, cyano, carboxyl, lower alkoxycarbonyl, lower haloalkyl, hydroxyl, lower alkoxy, lower hydroxyalkyl, lower alkoxyalkyl, lower haloalkoxy, amino, lower alkylamino, arylamino and nitro; and wherein R5 is selected from lower alkyl and amino; or a pharmaceutically-acceptable salt thereof.
Another preferred class of compounds consists of those compounds of Formula II wherein R1 is selected from lower alkyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxyalkyl, lower aralkylsulfonyl, lower arylthioalkyl, heteroarylalkoxyalkyl, lower heteroaryloxyalkyl, lower heteroarylthioalkyl, lower heteroarylalkylthioalkyl, lower aralkylthio, and lower aralkoxy; wherein R2 is selected from heteroaryl, cycloalkyl and aryl, wherein the heteroaryl, cycloalkyl and aryl radicals are substituted at a substitutable position with one or more radicals selected from hydrido, halo, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkyl, cyano, carboxyl, lower alkoxycarbonyl, lower haloalkyl, hydroxyl, lower alkoxy, lower hydroxyalkyl, lower alkoxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino and nitro; and wherein R5 is selected from lower alkyl-and amino; or a pharmaceutically-acceptable salt thereof.
Within Formula I there is a subclass of compounds of high interest represented by Formula III: 
wherein R1 is selected from lower alkyl, lower haloalkyl, lower aralkyl, lower heterocyclicalkyl, lower heteroaralkyl, acyl, cyano, mercapto, lower alkoxy, lower alkylthio, lower alkylthioalkyl, lower alkylsulfonyl, lower haloalkylsulfonyl, lower arylsulfonyl, halo, lower hydroxyalkyl, lower alkoxyalkyl, lower alkenyloxyalkyl, lower alkylcarbonyl, lower arylcarbonyl, lower aralkylcarbonyl, lower cyanoalkyl, lower aralkenyl, lower aminoalkyl, lower alkylaminoalkyl, lower N-arylaminoalkyl, lower N-alkyl-N-arylaminoalkyl, lower carboxyalkyl, lower alkoxycarbonylalkyl, lower alkoxycarbonyl, lower haloalkylcarbonyl, carboxyl, aminocarbonyl, lower alkylaminocarbonyl, lower alkylaminocarbonylalkyl, lower aralkoxy, lower aralkylthio, phenylsulfonyl, lower aralkylsulfonyl, lower heteroaralkoxy, lower heteroaralkylthio, lower heteroarylalkoxyalkyl, lower heteroaryloxyalkyl, lower heteroarylthioalkyl, lower heteroarylalkylthioalkyl, heteroaryloxy, heteroarylthio, lower arylthioalkyl, lower aryloxyalkyl, lower arylthio, aryloxy, lower aralkylthioalkyl, lower aralkoxyalkyl, lower alkoxyaralkoxyalkyl, aryl and heteroaryl, wherein the aryl and heteroaryl radicals are optionally substituted at a substitutable position with one or more radicals selected from halo, lower alkylthio, lower alkylsulfinyl, lower alkyl, cyano, lower haloalkyl, lower hydroxyl, lower alkoxy, lower: hydroxyalkyl and lower haloalkoxy; wherein R2 is selected from heteroaryl, lower cycloalkyl, lower cycloalkenyl, and aryl, wherein the heteroaryl, lower cycloalkyl, lower cycloalkenyl, and aryl radicals are substituted with one or more radicals selected from hydrido, halo, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, lower alkyl, cyano, carboxyl, lower alkoxycarbonyl, lower haloalkyl, hydroxyl, lower alkoxy, lower hydroxyalkyl, lower alkoxyalkyl, lower haloalkoxy, amino, lower alkylamino, arylamino and nitro; wherein R4 is selected from lower alkyl and acyl; and wherein R5 is selected from lower alkyl and amino; or a pharmaceutically-acceptable salt thereof.
Compounds of Formula I where R2 is heteroaryl would also be capable of inhibiting cytokines, such as TNF, IL-1, IL-6, and IL-8. As such, the compounds can be used in the manufacture of a medicament or in a method for the treatment for the prophylactic or therapeutic treatment of diseases mediated by cytokines, such as TNF, IL-1, IL-6, and IL-8.
The term xe2x80x9chydridoxe2x80x9d denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical or two hydrido radicals may be attached to a carbon atom to form a methylene (xe2x80x94CH2xe2x80x94) radical. Where used, either alone or within other terms such as xe2x80x9chaloalkylxe2x80x9d, xe2x80x9calkylsulfonylxe2x80x9d, xe2x80x9calkoxyalkylxe2x80x9d and xe2x80x9chydroxyalkylxe2x80x9d, the term xe2x80x9calkylxe2x80x9d embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are xe2x80x9clower alkylxe2x80x9d radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like. The term xe2x80x9chaloxe2x80x9d means halogens such as fluorine, chlorine, bromine or iodine. The term xe2x80x9chaloalkylxe2x80x9d embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. xe2x80x9cLower haloalkylxe2x80x9d embraces radicals having 1-6 carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. The term xe2x80x9chydroxyalkylxe2x80x9d embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one-or more hydroxyl radicals. More preferred hydroxyalkyl radicals are xe2x80x9clower hydroxyalkylxe2x80x9d radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. The terms xe2x80x9calkoxyxe2x80x9d and xe2x80x9calkoxyalkylxe2x80x9d embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms. More preferred alkoxy radicals are xe2x80x9clower alkoxyxe2x80x9d radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. The term xe2x80x9calkoxyalkylxe2x80x9d embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. More preferred alkoxyalkyl radicals are xe2x80x9clower alkoxyalkylxe2x80x9d radicals having one to six carbon atoms and one or two alkoxy radicals. Examples of such radicals include methoxymethyl, methoxyethyl, ethoxyethyl methoxybutyl and methoxypropyl. The xe2x80x9calkoxyxe2x80x9d or xe2x80x9calkoxyalkylxe2x80x9d radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide xe2x80x9chaloalkoxyxe2x80x9d or xe2x80x9chaloalkoxyalkylxe2x80x9d radicals. More preferred haloalkoxy radicals are xe2x80x9clower haloalkoxyxe2x80x9d radicals having one to six carbon atoms and one or more halo radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy. The term xe2x80x9ccyanoalkylxe2x80x9d embraces radicals having a cyano or nitrile (xe2x80x94CN) radical attached to an alkyl radicals as described above. More preferred cyanoalkyl radicals are xe2x80x9clower cyanoalkylxe2x80x9dradicals having one to six carbon atoms. Examples of such lower cyanoalkyl radicals include cyanomethyl, cyanopropyl, cyanoethyl and cyanobutyl. The term xe2x80x9ccycloalkylxe2x80x9d embraces saturated carbocyclic radicals having three to twelve carbon atoms. More preferred cycloalkyl radicals are xe2x80x9clower cycloalkylxe2x80x9d radicals having three to about eight carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term xe2x80x9ccycloalkenylxe2x80x9d embraces unsaturated cyclic radicals having three to ten carbon atoms. More preferred cycloalkenyl radicals are xe2x80x9clower cycloalkenylxe2x80x9d radicals having about five to about eight carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. The term xe2x80x9carylxe2x80x9d, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. The term xe2x80x9carylxe2x80x9d embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. The terms xe2x80x9cheterocyclicxe2x80x9d and xe2x80x9cheterocycloxe2x80x9d embrace saturated, partially saturated and unsaturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocylic group containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl, etc.]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl, etc.]. Examples of partially saturated heterocyclic radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole. The term xe2x80x9cheteroarylxe2x80x9d embraces unsaturated heterocyclic radicals. Examples of unsaturated heterocyclic radicals, also termed xe2x80x9cheteroarylxe2x80x9d radicals include unsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.] tetrazolyl [e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [1,5-b]pyridazinyl, etc.], etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.; unsaturated 3- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.] etc.; unsaturated. condensed heterocyclic group containing 1 to 2 oxygen atoms and. 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.] etc.; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl, etc.] and the like. The term also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuryl, benzothienyl, and the like. Said xe2x80x9cheterocyclicxe2x80x9d radicals may have 1 to 3 substituents such as lower alkyl, hydroxy, oxo, amino and lower alkylamino. More preferred heteroaryl radicals include five to six membered heteroaryl radicals. The term xe2x80x9cheterocyclicalkylxe2x80x9d embraces heterocyclic-substituted alkyl radicals. More preferred heterocyclicalkyl radicals are xe2x80x9clower heterocyclicalkylxe2x80x9d radicals having one to six carbon atoms and a heterocyclic radical. Examples include such radicals as pyrrolidinylmethyl. The term xe2x80x9calkylthioxe2x80x9d embraces radicals containing a linear or branched alkyl radical, of one to about ten carbon atoms attached to a divalent sulfur atom. More preferred alkylthio radicals are xe2x80x9clower alkylthioxe2x80x9d radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio. The term xe2x80x9calkylthioalkylxe2x80x9d embraces alkylthio radicals attached to an alkyl radical. More preferred alkylthioalkyl radicals are xe2x80x9clower alkylthioalkylxe2x80x9d radicals having alkyl radicals of one to six carbon atoms and an alkylthio radical as described above. Examples of such radicals include methylthiomethyl. The term xe2x80x9carylthioxe2x80x9d embraces radicals containing an aryl radical, attached to a divalent sulfur atom, such as a phenylthio radical. The term xe2x80x9carylthioalkylxe2x80x9d embraces arylthio radicals attached to an alkyl radical. More preferred arylthioalkyl radicals are xe2x80x9clower arylthioalkylxe2x80x9d radicals having alkyl radicals of one to six carbon atoms and an arylthio radical as described above. Examples of such radicals include phenylthiomethyl. The term xe2x80x9calkylsulfinylxe2x80x9d embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent xe2x80x94S(xe2x95x90O)xe2x80x94 radical. More preferred alkylsulfinyl radicals are xe2x80x9clower alkylsulfinylxe2x80x9d radicals having one to six carbon atoms. Examples of such lower alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, butylsulfinyl and hexylsulfinyl. The term xe2x80x9csulfonylxe2x80x9d, whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals xe2x80x94SO2xe2x80x94. xe2x80x9cAlkylsulfonylxe2x80x9d embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above. More preferred alkylsulfonyl radicals are xe2x80x9clower alkylsulfonylxe2x80x9d radicals having one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and propylsulfonyl. The xe2x80x9calkylsulfonylxe2x80x9d radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide xe2x80x9chaloalkylsulfonylxe2x80x9d radicals. More preferred haloalkylsulfonyl radicals are xe2x80x9clower haloalkylsulfonylxe2x80x9d radicals having one or more halo atoms attached to lower alkylsulfonyl radicals as described above. Examples of such lower haloalkylsulfonyl radicals include fluoromethylsulfonyl, trifluoromethylsulfonyl and chloromethylsulfonyl. The term xe2x80x9carylsulfonylxe2x80x9d embraces aryl radicals as defined above, attached to a sulfonyl radical. Examples of such radicals include phenylsulfonyl. The term xe2x80x9caralkylsulfonylxe2x80x9d embraces aralkyl radicals as defined above, attached to a sulfonyl radical. Examples of such radicals include benzylsulfonyl. The term xe2x80x9cheteroarylsulfonylxe2x80x9d embraces heteroaryl radicals as defined above, attached to a sulfonyl radical. Examples of such radicals include thienylsulfonyl, oxazolylsulfonyl and pyridylsulfonyl. The term xe2x80x9cheteroarylalkylsulfonylxe2x80x9d embraces heteroarylalkyl radicals as defined above, attached to a sulfonyl radical. Examples of such radicals include thienylmethylsulfonyl. The terms xe2x80x9csulfamylxe2x80x9d, xe2x80x9cminosulfonylxe2x80x9d and xe2x80x9csulfonamidylxe2x80x9d denotes NH2O2Sxe2x80x94. The term xe2x80x9cacylxe2x80x9d denotes a radical provided by the residue after removal of hydroxyl from an organic acid. Examples of such acyl radicals include formyl, alkanoyl and aroyl radicals. The terms xe2x80x9ccarboxyxe2x80x9d or xe2x80x9ccarboxylxe2x80x9d, whether used alone or with other terms, such as xe2x80x9ccarboxyalkylxe2x80x9d, denotes xe2x80x94CO2H. The term xe2x80x9ccarbonylxe2x80x9d, whether used alone or with other terms, such as xe2x80x9calkoxycarbonylxe2x80x9d, denotes xe2x80x94(Cxe2x95x90O)xe2x80x94. The term xe2x80x9calkoxycarbonylxe2x80x9d means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical. Preferably, xe2x80x9clower alkoxycarbonylxe2x80x9d embraces alkoxy radicals having one to six carbon atoms. Examples of such xe2x80x9clower alkoxycarbonylxe2x80x9d ester radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl. The term xe2x80x9caralkylxe2x80x9d embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are xe2x80x9clower aralkylxe2x80x9d radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. The aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy. The terms benzyl and phenylmethyl are interchangeable. The term xe2x80x9caralkenylxe2x80x9d embraces aryl-substituted alkenyl radicals. Preferable aralkenyl radicals are xe2x80x9clower aralkenylxe2x80x9d radicals having aryl radicals attached to alkenyl radicals having two to six carbon atoms. Examples of such radicals include phenylethenyl and diphenylethenyl. The aryl in said aralkenyl may be additionally substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy. The terms xe2x80x9calkylcarbonylxe2x80x9d, xe2x80x9carylcarbonylxe2x80x9d and xe2x80x9caralkylcarbonylxe2x80x9d include radicals having alkyl, aryl and aralkyl radicals, respectively, as defined above, attached via an oxygen atom to a carbonyl radical. More preferred alkylcarbonyl radicals are xe2x80x9clower alkylcarbonylxe2x80x9d radicals having one to six carbon atoms. Examples of such radicals include methylcarbonyl and ethylcarbonyl. More preferred aralkylcarbonyl radicals are xe2x80x9clower aralkylcarbonylxe2x80x9d radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such aralkylcarbonyl radicals include benzylcarbonyl. An example of an arylcarbonyl radical is phenylcarbonyl. The term xe2x80x9calkoxycarbonylalkylxe2x80x9d embraces radicals having xe2x80x9calkoxycarbonylxe2x80x9d, as defined above substituted to an alkyl radical. More preferred alkoxycarbonylalkyl radicals are xe2x80x9clower alkoxycarbonylalkylxe2x80x9d having lower alkoxycarbonyl radicals as defined above attached to one to six carbon atoms. Examples of such lower alkoxycarbonylalkyl radicals include methoxycarbonylmethyl. The term xe2x80x9chaloalkylcarbonylxe2x80x9d embraces radicals having a haloalkyl radical as described above attached to a carbonyl radical. More preferred radicals are xe2x80x9clower haloalkylcarbonylxe2x80x9d radicals where lower haloalkyl radicals, as described above are attached to a carbonyl radical. The term xe2x80x9ccarboxyalkylxe2x80x9d embrace radicals having a carboxy radical as defined above, attached to an alkyl radical. The alkanoyl radicals may be substituted or unsubstituted, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, trifluoroacetyl or the like, in which the preferable one is formyl, acetyl, propionyl or trifluoroacetyl. The term xe2x80x9cheteroaralkylxe2x80x9d embraces heteroaryl-substituted alkyl radicals. More preferred heteroaralkyl radicals are xe2x80x9clower heteroaralkylxe2x80x9d radicals having five to six membered heteroaryl radicals attached to one to six carbon atoms. Examples of such radicals include pyridylmethyl, quinolylmethyl, thienylmethyl, furylethyl and quinolylethyl. The heteroaryl in said heteroaralkyl may be additionally substituted with halo, alkyl, alkoxy, haloalkyl and haloalkoxy. The term xe2x80x9caryloxyxe2x80x9d embraces aryl radicals, as defined above, attached to an oxygen atom. The aryl in said aryloxy may be additionally substituted with one or more halo, alkyl, alkoxy, haloalkyl and haloalkoxy radicals. Examples of such radicals include phenoxy. The term xe2x80x9cheteroaryloxyxe2x80x9d embraces heteroaryl radicals as defined above attached to an oxygen radical. More preferred heteroaryloxy radicals are xe2x80x9clower heteroaryloxyxe2x80x9d radicals having five to six membered heteroaryl radicals. The term xe2x80x9caralkoxyxe2x80x9d embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. The term xe2x80x9caralkoxyalkylxe2x80x9d embraces alkyl radicals having one or more aralkoxy radicals attached to the alkyl radical, that is, to form monoaralkyloxyalkyl and diaralkyloxyalkyl radicals. The xe2x80x9caralkoxyxe2x80x9d or xe2x80x9caralkoxyalkylxe2x80x9d radicals may be further substituted on the aryl ring portion of the radical. More preferred aralkoxyalkyl radicals are xe2x80x9clower aralkoxyalkylxe2x80x9d having an alkoxy attached to one to six carbon atoms. Examples of lower aralkoxyalkyl radicals include benzyloxymethyl. The term xe2x80x9cheteroarylthioxe2x80x9d embraces radicals having heteroaryl radicals attached to a sulfur radical. More preferred heteroarylthio radicals are xe2x80x9clower heteroarylthioxe2x80x9d radicals having five to six membered heteroaryl radicals. Examples of such radicals include 2-furylthio, 2-thienylthio, 3-thienylthio, 4-pyridylthio and 3-pyridylthio. The term xe2x80x9calkoxyaralkoxyalkylxe2x80x9d embraces alkoxy substituted aralkoxyalkyl radicals. More preferred radicals have lower alkoxy substituted aralkoxyalkyl, where lower alkoxy is defined above. The terms xe2x80x9cheteroaralkylthioxe2x80x9d and xe2x80x9cheteroaralkylthioxe2x80x9d denote radicals having an heteroaryl radical attached to an alkylthio radical. More preferred heteroaralkylthio radicals are xe2x80x9clower heteroaralkylthioxe2x80x9d radicals having heteroaryl radicals attached to lower alkylthio radicals as described above. Examples of such radicals include furylmethylthiomethyl and quinolylmethylthioethyl. The term xe2x80x9cheteroarylalkylthioalkylxe2x80x9d denotes radicals having an heteroaryl radical attached to an alkylthio radical further attached through the sulfur atom to an alkyl radical. More preferred heteroarylalkylthioalkyl are xe2x80x9clower heteroarylalkylthioalkylxe2x80x9d radicals having lower heteroarylalkyl radicals as described above. Examples of such radicals include furylmethylthiomethyl and quinolylmethylthioethyl. The term xe2x80x9cheteroarylthioalkylxe2x80x9d denotes radicals having an heteroaryl radical attached to a sulfur atom further attached through the sulfur atom to an alkyl radical. More preferred heteroarylthioalkyl radicals are xe2x80x9clower heteroarylthioalkylxe2x80x9d having lower heteroarylthio radicals as described above. Examples of such radicals include thienylthiomethyl and pyridylthiohexyl. The term xe2x80x9caralkylthioxe2x80x9d embraces radicals having aralkyl radicals attached to a bridging sulfur atom. More preferred aralkylthio radicals are xe2x80x9clower aralkylthioxe2x80x9d radicals having the aryl radicals attached to one to six carbon atoms. Examples of such radicals include benzylthio and phenylethylthio. The term xe2x80x9caralkylthioalkylxe2x80x9d embraces radicals having aralkyl radicals attached to alkyl radicals through a bridging sulfur atom. More preferred aralkylthioalkyl radicals are xe2x80x9clower aralkylthioalkylxe2x80x9d radicals having the aralkylthio radicals attached to one to six carbon atoms. Examples of such radicals include benzylthiomethyl and phenylethylthiomethyl. The term xe2x80x9cheteroaryloxyalkylxe2x80x9d denotes radicals having an heteroaryl radical attached to an oxygen atom further attached through the oxygen atom to an alkyl radical. More preferred heteroaryloxyalkyl radicals are xe2x80x9clower heteroaryloxyalkylxe2x80x9d radicals having five to six membered heteroaryl radicals. Examples of such radicals include furylbutoxyethyl, pyridyloxymethyl and thienyloxyhexyl. The term xe2x80x9caminoalkylxe2x80x9d embraces alkyl radicals substituted with amino radicals. More preferred aminoalkyl radicals are xe2x80x9clower aminoalkylxe2x80x9d having one to six carbon atoms. Examples include aminomethyl, aminoethyl and aminobutyl. The term xe2x80x9calkylaminoalkylxe2x80x9d embraces aminoalkyl radicals having the nitrogen atom substituted with at least one alkyl radical. More preferred alkylaminoalkyl radicals are xe2x80x9clower alkylaminoalkylxe2x80x9d having one to six carbon atoms attached to a lower aminoalkyl radical as described above. More preferred alkylamino radicals are xe2x80x9clower alkylaminoxe2x80x9d radicals having one or two alkyl radicals of one to six carbon atoms, attached to a nitrogen atom. The term xe2x80x9calkylaminoxe2x80x9d denotes amino groups which have been substituted with one or two alkyl radicals. Suitable xe2x80x9calkylaminoxe2x80x9d may be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like. The term xe2x80x9calkylaminocarbonylxe2x80x9d embraces alkylamino radicals, as described above, to a carbonyl radical. More preferred alkylaminocarbonyl radicals are xe2x80x9clower alkylaminocarbonylxe2x80x9d having lower alkylamino radicals, as described above; attached to a carbonyl radical. Examples of such radicals include N-methylaminocarbonyl and N,N-dimethylcarbonyl. The term xe2x80x9carylaminoxe2x80x9d denotes amino groups which have been substituted with one or two aryl radicals, such as N-phenylamino. The xe2x80x9carylaminoxe2x80x9d radicals may be further substituted on the aryl ring portion of the radical. The terms xe2x80x9cN-arylaminoalkylxe2x80x9d and xe2x80x9cN-aryl-N-alkyl-aminoalkylxe2x80x9d denote amino groups which have been substituted with one aryl radical or one aryl and one alkyl radical, respectively, and having the amino group attached to an alkyl radical. More preferred arylaminoalkyl radicals are xe2x80x9clower arylaminoalkylxe2x80x9d having the arylamino radical attached to one to six carbon atoms. Examples of such radicals include N-phenylaminomethyl and N-phenyl-N-methylaminomethyl. The term xe2x80x9caminocarbonylxe2x80x9d denotes an amide group of the formula xe2x80x94C(xe2x95x90O)NH2. The term xe2x80x9calkylaminocarbonylalkylxe2x80x9d denotes an aminocarbonyl group which has been substituted with one or two alkyl radicals. More preferred are xe2x80x9clower alkylaminocarbonylalkylxe2x80x9d having lower alkylaminocarbonyl radicals as described above attached to one to six carbon atoms. The term xe2x80x9caryloxyalkylxe2x80x9d embraces alkyl radicals having one or more aryloxy radicals, aryl radicals attached to a divalent oxygen atom, attached to the alkyl radical, that is, to form monoaryloxyalkyl and diaryloxyalkyl radicals. The more preferred aryloxyalkyl radicals are xe2x80x9clower aryloxyalkylxe2x80x9d radicals having aryloxy radicals attached to one to six carbon atoms. Examples include phenoxymethyl. The terms xe2x80x9cheteroaralkoxyalkylxe2x80x9d and xe2x80x9cheteroarylalkoxyalkylxe2x80x9d embrace alkyl radicals having one or more heterocyclic radicals attached to an alkoxy radical, further attached to the alkyl radical. More preferred heteroaralkoxyalkyl radicals are xe2x80x9clower heteroaryl alkoxyalkyl radicals having five to six membered heteroaryl radicals. Examples of such radicals include 2-thienylmethoxymethyl.
The present invention comprises a pharmaceutical composition comprising a therapeutically-effective amount of a compound of Formula I in association with at least one pharmaceutically-acceptable carrier, adjuvant or diluent.
The present invention also comprises a method of treating inflammation or inflammation-associated disorders in a subject, the method comprising administering to the subject having or susceptible to such inflammation or disorder a therapeutically-effective amount of a compound of Formula I.
Also included in the family of compounds of Formula I are the pharmaceutically-acceptable salts thereof. The term xe2x80x9cpharmaceutically-acceptable saltsxe2x80x9d embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula I may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethylsulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic sulfanilic, stearic, cyclohexylaminosulfonic, algenic, xcex2-hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I include metallic salts made from aluminum, calcium, lithium, magnesium, -potassium, sodium and zinc or organic salts made from N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding compound of Formula I by reacting, for example, the appropriate acid or base with the compound of Formula I.
The compounds of the invention can be synthesized according to the following procedures of Schemes I-VII, wherein the R1-R5 substituents are as defined for Formula I-III, above, except where further noted. 
The subject imidazole compounds 6 of this invention may be synthesized according to the sequence outlined in Scheme I. Aldehyde 1 may be converted to the protected cyanohydrin 2 by reaction with a trialkylsilyl cyanide, such as trimethylsilyl cyanide (TMSCN) in the presence of a catalyst such as zinc iodide (ZnI2) or potassium cyanide (KCN). Reaction of cyanohydrin 2 with a strong base followed by treatment with aldehyde 3 and using both acid and base treatments, in that order, on workup gives enol 4. Examples of strong bases suitable for this reaction are lithium diisopropylamide (LDA) and lithium hexamethyldisilazane. Enol 4 may be converted to diketone 5 by reaction with a suitable oxidizing agent, such as bismuth oxide or manganese dioxide, or by a Swern oxidation using dimethyl sulfoxide (DMSO) and trifluoroacetic anhydride. Diketone 5 may be obtained directly by reaction of the anion of cyanohydrin 2 with a substituted acid halide (where X is halo). Any of compounds 4 and 5 may be used as intermediates for conversion to imidazoles 6 according to chemical procedures known by those skilled in the art and described by M. R. Grimmett, xe2x80x9cAdvances in Imidazole Chemistryxe2x80x9d in Advances in Heterocyclic Chemistry, 12, 104 (1970). The conversion of 5 to imidazoles 6 is carried out by reaction with ammonium acetate and an appropriate aldehyde (R1CHO) in acetic acid. Enol 4 may be converted to imidazoles 6 by reaction with formamide. In addition, enol 4 may be converted to imidazoles by first acylating with an appropriate acyl group (R1COxe2x80x94) and then treating with ammonium hydroxide. 
The subject imidazole compounds 11 of this invention may be synthesized according to the sequence outlined in Scheme II. Reaction of cyanohydrin 2 with a strong base followed by treatment with benzaldehyde 7 (where R5 is alkyl) and using both acid and base treatments, in that order, on workup gives benzoin 8. Examples of strong bases suitable for this reaction are lithium diisopropylamide (LDA) and lithium hexamethyldisilazane. Benzoin 8 may be converted to benzil 9 by reaction with a suitable oxidizing agent, such as bismuth oxide or manganese dioxide, or by a Swern oxidation using dimethyl sulfoxide (DMSO) and trifluoroacetic anhydride. Benzil 9 may be obtained directly by reaction of the anion of cyanohydrin 2 with a substituted benzoic acid halide (where X is halo) Any of compounds 8 and 9 may be used as intermediates for conversion to imidazoles 10 (where R5 is alkyl) according to chemical procedures known by those skilled in the art and described by M. R. Grimmett, xe2x80x9cAdvances in Imidazole Chemistryxe2x80x9d in Advances in Heterocyclic Chemistry, 12, 104 (1970). The conversion of 9 to imidazoles 10 is carried out by reaction with ammonium acetate and an appropriate aldehyde (R1CHO) in acetic acid. Benzoin 8 may be converted to imidazoles 10 by reaction with formamide. In addition, benzoin 8 may be converted to imidazoles by first acylating with an appropriate acyl group (R1COxe2x80x94) and then treating with ammonium hydroxide. Those skilled in the art will recognize that the oxidation of the sulfide (where R5 is methyl) to the methylsulfone (xe2x80x94SO2CH3) may be carried out at any point along the way beginning with compounds 8, and including oxidation of imidazoles 10, using, for examples, reagents such as hydrogen peroxide in acetic acid, m-chloroperoxybenzoic acid (MCPBA) and potassium peroxymonosulfate (OXONE(copyright)). 
Alternative syntheses of benzoins and benzils may be carried out as described in Scheme III. Acylation of a thiobenzene derivative with an appropriately substituted acetic acid 12 using an acidic catalyst yields desoxybenzoin 13. Some suitable acidic catalysts include polyphosphoric acid (PPA), sulfuric acid, titanium tetrachloride, ferric chloride and stannic chloride. The resulting desoxybenzoin 13 may be halogenated to give haloketone 14 (where X is halo). Treatment of compound 14 with either water in a suitable co-solvent such as acetone, or with a. carboxylate salt, followed by saponification with base, yields benzoin 15. Examples of bases suitable for saponification include sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide and ammonium hydroxide. Examples of appropriate carboxylate salts include sodium acetate and sodium benzoate. Compound 15 is converted to benzil 9 by reaction with a suitable oxidizing agent such as bismuth oxide or manganese dioxide. Alternatively, benzil 9 may be synthesized directly from desoxybenzoin 13 by treatment with an appropriate oxidizing agent, such as selenious acid (H2SeO3).
Haloketone 14 may be converted to imidazoles 10 by reaction either with formamide or with amidines. 
Scheme III outlines yet another outlines yet another method for the synthesis of benzil 9. Reaction of a suitable acetic acid derivative 16 with an aromatic aldehyde 7 in acetic anhydride yields unsaturated acid 17. Acid 17 is converted to acyl azides 18 by reaction with diphenylphosphoryl azide (DPPA) in the presence of a base such as triethylamine (Et3N) or by reaction of an activated carboxyl derivative of 17, such as an acid chloride or anhydride, with sodium azide. Decomposition of the acyl azide 18 by thermolysis, followed by hydrolysis with aqueous acid yields desoxybenzoin 19. Compound 19 may be converted to benzil 9 by oxidation according to procedures discussed in Schemes II-III. 
The compounds of the invention can be prepared according to the procedures in Scheme V. The subject imidazoles 24 are obtained from the condensation of diketones 23 with aldehydes R1CHO in the presence of acetic acid and ammonium acetate, as previously described. Scheme V differs from previous synthetic routes in that it employs an xcex1-diketone 23 that is obtained by oxidation of the olefinic intermediate 22. This transformation is conveniently accomplished in one pot subjecting the olefin to potassium permanganate oxidation in acetic anhydride, according to a method of stilbene oxidation developed by Sharpless, et al. [J. Am. Chem. Soc., 93, 3303 (1971)]. One may reduce the requirement for acetic anhydride by using a cosolvent, such as dioxane, ether, or methylene chloride. Oxidative sequences involving catalytic permanganate; catalytic osmium tetroxide followed by Swern oxidation; or epoxidation followed by oxidative rearrangement present alternatives to the conditions described.
Olefin 22 may be obtained using Wittig technology or other coupling protocols, such as transition metal mediated cross-coupling, silicon-based (Peterson) olefination, or sulfone-based (Julia) coupling. The commercial intermediate 25 (X=Cl) in the present scheme is transformed into an activated phosphorus compound, for example, a triphenylphosphonium salt. The phosphorus species 26 is deprotonated with a strong base, lithium ethoxide, generated in situ from n-butyllithium and ethanol. Other bases, such as sodium hydroxide or potassium t-butoxide present alternatives. A primarily aprotic medium could be employed, such as potassium tert-butoxide in tetrahydrofuran or sodium amide in dioxane. R2CHO represents an aryl aldehyde, such as benzaldehyde; an alkyl or cycloalkyl aldehyde, such as cyclohexanecarboxaldehyde; or a heterocyclic aldehyde, such as thiophene carboxaldehyde. It is recognized that the intermediate methyl sulfone 25 could be replaced with a different (e.g. ethyl sulfone) or sulphonamide with similar results.
Olefin 22 may also be obtained by allowing a suitable phosphonium salt 21 (X=Cl, Br, OTs, or I) to react in the presence of strong base, such as lithium ethoxide with 4-(thiomethyl)benzaldehyde. Oxidation of the sulfur atom to the sulfone is conveniently accomplished with Oxone(copyright) at this stage, but could be accomplished with other reagents, such as hydrogen peroxide or m-chloroperbenzoic acid, or could be effected at another place in the sequence. The oxidation step could be entirely eliminated by employing 4-(methylsulphonyl)benzaldehyde in the place of 4-(thiomethyl)benzaldehyde. 
Synthetic Scheme VI shows the three step procedure used to prepare sulfonamide antiinflammatory agents 28 and the two step procedure used to prepare fluoromethyl sulfone antiinflammatory agents 29 from their corresponding methyl sulfones 27. In step one, THF solutions of the methyl sulfones 27 at xe2x88x9278xc2x0 C. are treated with an alkyllithium reagent, e.g., methyllithium, n-butyllithium, lithium diisopropylamide (LDA), etc. In step two, the anions generated in step one are treated with an organoborane, e.g., triethylborane, tributylborane, etc., at xe2x88x9278xc2x0 C. then allowed to warm to ambient temperature prior to stirring at reflux. An alternative to the boron chemistry involves room temperature alkylation, such as with trimethylsilylmethylhalides, followed by treatment with tetrabutylammonium fluoride (1M in THF). In step three, an aqueous solution of sodium acetate and hydroxylamine-O-sulfonic acid is added to provide the corresponding sulfonamide antiinflammatory agents 28 of this invention. Alternatively, the anion solutions generated in step one may be warmed to 0xc2x0 C. and treated with N-fluorodibenzenesulfonamide to provide the corresponding fluoromethyl sulfone antiinflammatory agents 29 of this invention. 
Synthetic Scheme VII outlines further modications at position 2 of the imidazole compounds of this invention. Compound 30 may be obtained via the condensation of benzoin 8 with formamide as discussed above. The parent imidazole 30, maybe converted to the ethoxyethyl derivatives 31 by treatment with ethylvinylether in the presence of an acid catalyst. Examples of suitable acid catalysts are dichloroacetic acid, p-toluenesulfonic acid, methanesulfonic acid and hydrogen chloride. Alternatively the ethoxyethyl group may be incorporated by chemical procedures known to those skilled in the art and described by T. S. Manoharan and R. S. Brown in J. Org. Chem., 53, 1107-1110 (1988). Due to the tautomeric nature of the nitrogen atom, two compounds 31 are obtained at the end of this process. Both compounds 31 are carried on to subsequent steps as a mixture because this group is ultimately removed and upon removal one compound is obtained from the reaction sequence of interest. A series of acyl derivatives can be obtained by conversion of 31 into 32 and then 33 by lithiation via the process of Manoharan and Brown, followed by treatment of the resulting lithium anion with amides such as dimethylformamide (R6=H, R7 and R8=CH3), dimethyl acetamide(R6,R7, R8=CH3) or with amides where R7 and R8=OMe and CH3 and wherein R6 may include hydrogen, lower alkyl, aryl, aralkyl, and haloalkyl. Subsequent treatment with Oxone(copyright) results in compounds 33, where R6 is as defined above. The preparation of these amides involves the treatment of the appropriate carboxylic acid with N,O-dimethylhydroxyamine chloride in the presence of triethylamine, and 2-chloromethylpyridinium iodide at room temperature in methylene chloride. The preparation of the amide where R7 and R8 are OMe and methyl, and R6 is CF3 can be accomplished by those skilled in art by following the published procedure in J. Org. Chem,. 56, 4260 (1991). Finally, the lithium anion may be treated with other electrophiles, for example, trifluoroacetone or N-fluorodibenzenesulfonamide resulting in compounds where imidazole position 2 is [CH3(OH)CF3] or phenylsulfonyl 38, respectively. If further modification of the acyl group in compounds 32 is desired, the imidazole nitrogen at position 1 is left protected. This process is exemplified by the conversion of compounds 32 into 34, 35, 36, 37 and 38 where R6 is defined as stated above. The conversion of 32 into 34 can be performed by treatment of compound 32 with a reducing agent followed by treatment with Oxone(copyright). Some examples of reducing agents are sodium borohydride, lithium borohydride, zinc borohydride, lithium triethylborohydride, RED-AL, borane, alane, and diisopropylaluminum hydride. To synthesize ether compounds 35 (R9 is lower alkyl, alkenyl or aralkyl), ketones 32 are reduced to the corresponding alcohols using a suitable reducing agent as defined above. The resulting alcohol is treated with a strong base, such as sodium hydride or lithium hydride in a suitable solvent, such as dimethylformamide, dimethylsulfoxide or tetrahydrofuran, and then reacted with the appropriate alkyl, aralkyl or alkenyl halide. Oxidation of the sulfide to the methyl sulfone results in concomitant loss of the nitrogen protecting group to produce compounds 35. The conversion of compound 32 to 37 may be carried out by those that are skilled in the art using procedures described by Susan C. Sondej and John A. Katzenellenbogen [J. Org Chem., 51, 3508-3513 (1986).